Autoimmune diabetes is a regulated disease. There are distinct lags before the initiation of insulitis (checkpoint-I) and between the development of insulitis and diabetes (checkpoint-2). These pauses are evident in the NOD mouse model of diabetes, but are most easily studied in the BDC2.5 T cell receptor transgenic model. This proposal focuses on checkpoint-1. Naive diabetogenic T cells do not first encounter their pancreatic-islet B-cell specific antigen in the islets, themselves, but rather in the lymph nodes directly draining them. A likely scenario is that dendritic cells located in the islets somehow pick up beta-cell proteins; the now-activated cells migrate to the pancreatic lymph nodes, at the same time processing the internalized proteins to peptides, displaying the peptides in major histocompatibility complex class II molecules at the cell surface, and upregulating costimulatory molecules; the now-mature dendritic cells stimulate naive diabetogenic T cells circulating through the nodes, prompting them to migrate through the tissues; finally, the roving T cells re-encounter their cognate antigen on dendritic cells located in the islets, leading to their re-stimulation and retention. Checkpoint-1 reflects an impediment in this scenario: for some reason, in very young mice, B-cell-specific antigens are not made available to murine T cells circulating through the pancreatic lymph node. This application aims to identify the impediment in very young mice, and to determine how it is eventually lifted. More specifically, it describes experiments that will: i) determine whether a wave of islet-beta-cell death known to occur in juvenile rodents is accompanied by dendritic cell engulfment of beta-cell proteins and their activation; ii) assess the role of cell death-signalling molecules, most particularly caspase-12, in checkpoint-1; and iii) establish whether or not changes in dendritic cell subsets in the first weeks after birth play any role in checkpoint-1. These studies should illuminate the events surrounding the triggering of autoimmune diabetes, providing a framework for elucidating the differences between susceptible and resistant individuals, and perhaps providing new leads for interventional drug targets.